Sex-specific signatures of brain-wide induction of ΔFOSB and altered co-activation networks in a mouse model for exercise training

ABSTRACT Physical exercise training promotes brain health, yet the underlying mechanisms remain incompletely understood. Repeated neuronal activation results in accumulation of the transcription factor ΔFOSB, a long-lived splice variant of FOSB. We have previously demonstrated in rats that long-term voluntary wheel running (VWR), a behavioral paradigm that mimics exercise training in humans, altered ΔFOSB expression in a brain-wide manner, and that it reorganized co-activation networks. Here, we used a similar approach, now in mice, to map neuronal activation patterns following long-term VWR. Young-adult male and female C57BL/6J OlaHsd mice were allowed to run for four weeks on horizontal wheels, after which ΔFOSB immunoreactivity was quantified across 46 brain regions associated with stress regulation, cognition and reward-related behavior. Subsequently, network analysis was applied to assess VWR-mediated changes in patterns of interregional ΔFOSB co-activation and network topology. Male and female mice ran equal distances and VWR blunted bodyweight gain and final fat mass in both sexes. VWR modulated ΔFOSB expression across several cortical, striatal, hippocampal and thalamic regions. Network analysis revealed a sex-specific network reorganization, with reduced overall network density and increased cortical centrality in males, and greater global efficiency ( i.e. small-worldness) in females. Thus, VWR induced large-scale, sex-dependent adaptations in brain (in)activation, reshaping network organization in distinct ways across sexes. Because ΔFOSB regulates many target genes, our findings indicate that long-term VWR induces widespread transcriptional alterations throughout the mouse brain. More focused follow-up studies are required to investigate the impact of these specific alterations on stress regulation, cognition and reward-related behavior. SIGNIFICANCE STATEMENT Exercise training promotes brain health, but the underlying mechanisms remain elusive. Here, we studied ΔFOSB, a very stable transcription factor involved in neuroplasticity, after four weeks of running in mice. We show this altered ΔFOSB expression in a subset of 46 brain regions implicated in stress regulation, cognition and reward, notably with sex-specific signatures. This was accompanied by specific changes in ΔFOSB co-activation networks, including decreased network density and increased cortical centrality in males, and greater network efficiency in females. Our mouse ΔFOSB brain map following running improves our understanding of how exercise training impacts brain plasticity and offers a framework for more mechanistic future studies into running-mediated changes in stress regulation, cognition and reward-related behavior.